A 69-year-old man was admitted for surgical management of a T4aN3bM0 laryngopharyngeal squamous cell carcinoma. He had a history of Crohn disease, for which he had undergone bowel resection and active smoking (50 pack-years).
Emergency tracheostomy was performed 1 month before total laryngopharyngectomy with radial forearm free flap reconstruction, and a gastrostomy was placed 1 week later. At the time of surgery, the patient had lost 15 kg over a period of 6 months due to intense dysphagia, and gastrostomy refeeding was not initiated before surgery. Preanesthetic cardiovascular and pulmonary cardiovascular and pulmonary assessments were within normal limits. The patient’s weight and height were 54 kg and 170 cm, respectively, with a body mass index (BMI) of 18.68 kg/m2 and an ideal body weight of 66 kg. The patient had no personal or family history of anesthesia-related complications. Preoperative blood tests showed mild anemia (hemoglobin [Hb] 9.8 g·dL−1), no electrolyte abnormalities, and normal renal function, transaminases, and bilirubin. A nutritional workup and serum albumin assay were not performed. Doppler ultrasound of carotid arteries was normal.
No premedication was administered to the patient before arrival in the operating room, where monitors, including electrocardiography, invasive blood pressure monitoring by right radial artery catheterization, pulse oximetry, bispectral index (BIS), temperature, and neuromuscular function monitors, were placed. After preoxygenation, general anesthesia was induced using target-controlled infusions (TCI) of propofol and remifentanil, combined with intravenous boluses of lidocaine 1.5 mg·kg−1, ketamine 0.3 mg·kg−1, and atracurium 0.5 mg·kg−1. Induction doses were all based on actual body weight. A 33-Fr polyvinyl chloride (PVC) cuffed Montandon tube was inserted into the tracheostomy orifice, and the lungs were mechanically ventilated with end-tidal carbon dioxide (Etco2) ranging between 35 and 40 mm Hg. Anesthesia was maintained using continuous intravenous infusions of lidocaine 1.5 mg·kg−1·hour−1 and ketamine 0.15 mg·kg−1·hour−1 (ideal body weight) combined with TCI of propofol and remifentanil titrated to maintain BIS 50 and hemodynamic parameters within 20% of baseline values with mean arterial pressure (MAP) >70 mm Hg. Induction of anesthesia revealed clear clinical signs of hypovolemia, with pulse pressure variation (PPV) >25%, concentrated urine, and transient hypotension on initiation of positive pressure ventilation. Hemodynamic parameters returned to normal after fluid loading with 2 L of lactated Ringer’s solution and injections of ephedrine 12 mg plus phenylephrine 100 µg during the first 30 minutes of surgery. The patient subsequently remained hemodynamically stable throughout surgery, which lasted 8 hours. He received a total of 4.5 L of lactated Ringer’s solution, 500 mL of saline, and 500 mL of hydroxyethyl starch with 1500 mL of blood transfusion to compensate for dilution anemia (Hb 7 g·dL−1). Total doses of remifentanil, lidocaine, and ketamine were 808 µg, 868 mg, and 72 mg, respectively. Propofol and lidocaine were maintained until the end of surgery. Ketamine was stopped 1 hour before the completion of surgery. Paracetamol 1000 mg, ketoprofen 100 mg, and morphine 5 mg were administered at the end of the surgical procedure. Residual neuromuscular blockade (train-of-four [TOF] 70%) was reversed by neostigmine 2.5 mg and atropine 0.75 mg. After full recovery of neuromuscular function and BIS ranging between 50 and 65, the patient was transferred to the postanesthesia care unit (PACU) with satisfactory spontaneous breathing (via the tracheostomy cannula) but with no signs of recovery of consciousness.
One hour after discontinuing all sedative medications, the patient remained deeply sedated. Blood samples were drawn to assay serum electrolytes. Blood glucose, kidney and liver function tests, and pH and arterial blood gases (ABG) were normal. Severe hypoalbuminemia (albumin: 18 g·L−1) and hypoproteinemia (total protein: 35 g·L−1) were detected. Peripheral venous access sites were checked for possible subcutaneous extravasation of anesthetic agents and delayed absorption to explain persistent sedation. Despite the low doses of intravenous opioids, we decided to test the effect of an intravenous bolus injection of naloxone 0.4 mg. Thirty seconds after injection, the patient experienced a transient “awakening phase” lasting 20 seconds, during which he moved all 4 limbs and opened his eyes, before returning to a state of deep sedation (Glasgow Coma Scale 6). He did not have any clonic movements or arrhythmias. A second injection of naloxone at the same dosage 5 minutes later induced exactly the same clinical effects, while a third injection and continuous infusion of naloxone had almost no effect. The patient showed no signs of naloxone-related side effects (ie, sympathetic surge or pulmonary edema). Three hours after the last anesthetic agents, the patient remained deeply sedated. He finally regained consciousness 4 hours after the end of surgery. Neurological examination, performed by the senior anesthesiologist, was normal. The patient did not complain of any pain and had no memory of his PACU stay. Contrast-enhanced brain computed tomography (CT) scan performed before transfer to the ward did not reveal ischemic or hemorrhagic zones or cerebral edema. The rest of the patient’s postoperative stay was uneventful. No long-term effects were noted 1 month after discharge from the hospital.
The patient provided his written consent to publish this case report.
One of the etiologies for delayed awakening after general anesthesia is neurovascular compromise occurring during anesthesia. Neurovascular compromise requires urgent diagnosis and treatment. In the case reported here, the site of surgical resection was close to large neck arteries, and the surgical position required neck extension. However, the postoperative contrast-enhanced CT scan showed no signs of ischemia.
Another possible explanation is Wernicke encephalopathy, which should be suspected in nonalcoholic patients, especially in the setting of malignancy, malnutrition, and surgery,1 all of which were present in this case. However, spontaneous resolution of the symptoms without thiamine administration was inconsistent with this diagnosis.
Delayed awakening after general anesthesia can also be explained by the residual effects of hypnotic drugs. Many publications have reported that subcutaneous or intramuscular injections of anesthetics can delay recovery from anesthesia.2 In the present case, examination of all venous access sites did not reveal signs of extravasation.
Prolonged sedative effects of anesthetic agents may also result from true or relative overdosage of anesthetic agents. True overdosage of sedative agents can be eliminated in this case because all sedative agents were administered according to the recommended dosage regimens. Moreover, intraoperative BIS was within normal limits, suggesting the absence of massive overdosage. In view of the effects of the first intravenous bolus of naloxone, we initially thought that the patient may have experienced an opioid overdose. Several cases of delayed awakening due to miscalculation of the dose of remifentanil have been reported in the literature.3 In the present case, the dosages of both remifentanil and morphine were appropriate, and the effect of the naloxone bolus, although intense, was very brief. Interestingly, some authors have reported several cases in which naloxone was partially effective to reverse nonopioid-induced coma.4
Relative overdosage of intravenous agents was certainly responsible for the delayed awakening observed in our case. Although the patient had lost weight over several months before surgery, no preoperative nutritional assessment was performed. Unfortunately, nutritional screening and management are often neglected, despite evidence and recognition of their positive impact on patient outcomes.5 In fact, oral nutritional supplements for as little as 7 days preoperatively can drastically change the postoperative course.6 In the present case, postoperative laboratory tests revealed very low plasma albumin of 18 g·L−1 secondary to malnutrition, possibly aggravated by initial fluid loading to correct hypovolemia. Such a low plasma albumin concentration is associated with increased free fractions of anesthetic agents, resulting in modified pharmacodynamics. Propofol is highly bound to albumin and erythrocytes.7 In the present case, hemodilution-aggravated anemia and hypoalbuminemia increased the free fraction of propofol and therefore probably resulted in delayed recovery. Lidocaine, on the other hand, is highly bound to alpha-1-acid glycoprotein, also known as ΑGP or AAG.8 In undernourished patients, the blood AGP concentration is not different from that of normally nourished patients.9 Although lidocaine overdosage can lead to delayed recovery,10 relative propofol overdosage, therefore, remains a more likely etiology in this case. Finally, ketamine has a low protein binding of 20%–30%,11 and its pharmacokinetics are therefore less likely to be affected by malnutrition. Low plasma albumin may also have affected blood–brain barrier permeability, as hydrostatic pressure in blood vessels inducing fluid movement into the interstitial space is normally counterbalanced by colloid oncotic pressure maintaining fluid in the intravascular space. Severe hypoalbuminemia may, therefore, have lowered the intravascular oncotic pressure, predisposing to cerebral edema that may have participated in delayed recovery from anesthesia. Brain CT scan did not demonstrate signs of acute cerebral edema, but it was only performed after the patient had fully regained consciousness.
In conclusion, we report a case of delayed awakening from general anesthesia most likely explained by relative overdosage of sedative anesthetic drugs due to profound hypoalbuminemia. This case highlights the importance of preoperative malnutrition screening and management, which is highly recommended. Furthermore, in the presence of preoperative hypoalbuminemia, we recommend intraoperative monitoring of plasma albumin, particularly when large volumes of fluid resuscitation are required, and subsequent reduction of anesthesia maintenance doses or albumin supplementation.
Name: Mary Saad, MD.
Contribution: This author helped draft the article and approved the version submitted.
Name: Bénédicte Le Clec’h.
Contribution: This author helped draft the article and approved the version submitted.
Name: Gilles Dhonneur, PhD.
Contribution: This author helped revise the article and approved the version submitted.
This manuscript was handled by: BobbieJean Sweitzer, MD, FACP.
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